1. Field of the Invention
This invention relates to muscarinic receptor antagonists, especially certain 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives, pharmaceutical compositions containing them, and methods for their use as therapeutic agents.
2. Background of the Invention
Muscarinic receptor antagonists prevent the effects of acetylcholine by blocking its binding to muscarinic cholinoceptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells in peripheral ganglia and in the central nervous system, and predominantly have been employed to inhibit effects of parasympathetic nervous system activity. Thus, muscarinic receptor antagonists have far reaching physiological effects, and drugs which selectively interact with muscarinic receptors have an array of therapeutic applications. For example, muscarinic receptor antagonists have been employed in the treatment of various disorders in the gastrointestinal tract, genitourinary tract, respiratory tract, cardiovascular system, central nervous system, and have been shown to be useful in anesthesiology and ophthalmology.
Muscarinic receptor antagonists have been shown to be useful in treating various gastrointestinal disorders, including a wide variety of conditions that involve increased spasticity or motility of the gastrointestinal tract, for example diarrhea. These agents can reduce tone and motility if the conditions are due to excessive smooth muscle contractions.
Muscarinic receptor antagonists have been shown to be useful in treating various genitourinary tract disorders. These agents have been shown to lower intravesical pressure, increase bladder capacity, and reduce the frequency of urinary bladder contractions by antagonizing the parasymathetic control of this organ.
Muscarinic receptor antagonists have been shown to be useful in treating various respiratory tract disorders, particularly including those conditions that reduce secretion in both the upper and lower respiratory tracts and induce bronchial dilation. These agents can have beneficial effects when obstruction of the airway is associated with, for example, chronic bronchitis, chronic obstructive pulmonary disease, bronchial asthma or emphysema.
Muscarinic receptor antagonists have been shown to be useful in treating various cardiovascular disorders, for example, including those conditions where excessive vagal tone causes sinus or nodal bradycardia.
Muscarinic receptor antagonists have been shown to be useful in treating central nervous system disorders. These agents have been shown to be efficacious in previous dystonias or Parkinsonian symptoms, and have been highly effective in preventing motion sickness.
Muscarinic receptor antagonists have been shown to be useful in anesthesiology, particularly by inhibiting excessive salivation and secretions of the respiratory tract induced by administration of general anesthetic agents, and their concomitant bronchodilator action. They have also been shown to be useful in ophthalmology to produce mydriasis and cycloplegia when applied locally to the eye.
These and other therapeutic uses are described in Goodman & Gillman's, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996; Chapter 7, pages 148-160.